title: Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase.
abstract: Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2- and PI3K-dependent cancers.
authors.affiliation: Department of Medicine, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, and Vanderbilt University Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Garrett
authors.forename: María Graciela
authors.initials: MG
authors.lastname: Olivares
authors.forename: Cammie
authors.initials: C
authors.lastname: Rinehart
authors.forename: Nara D
authors.initials: ND
authors.lastname: Granja-Ingram
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.forename: Anindita
authors.initials: A
authors.lastname: Chakrabarty
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Eliot
authors.initials: E
authors.lastname: McKinely
authors.forename: H C
authors.initials: HC
authors.lastname: Manning
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human